Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJO86CJ)

• DOT Name: E3 ubiquitin-protein ligase RNF128 (RNF128)
• Synonyms: EC 2.3.2.27; Gene related to anergy in lymphocytes protein; GRAIL; RING finger protein 128; RING-type E3 ubiquitin transferase RNF128
• Gene Name: RNF128
• Related Disease:
  Barrett esophagus
  Esophageal squamous cell carcinoma
  Familial multiple trichoepithelioma
  Hypospadias
  Melanoma
  Neoplasm
  Systemic lupus erythematosus
  Ulcerative colitis
• UniProt ID: RN128_HUMAN
• PDB ID: 3ICU
• EC Number: 2.3.2.27
• Pfam ID: PF02225 ; PF13639
• Sequence:
  MGPPPGAGVSCRGGCGFSRLLAWCFLLALSPQAPGSRGAEAVWTAYLNVSWRVPHTGVNR
  TVWELSEEGVYGQDSPLEPVAGVLVPPDGPGALNACNPHTNFTVPTVWGSTVQVSWLALI
  QRGGGCTFADKIHLAYERGASGAVIFNFPGTRNEVIPMSHPGAVDIVAIMIGNLKGTKIL
  QSIQRGIQVTMVIEVGKKHGPWVNHYSIFFVSVSFFIITAATVGYFIFYSARRLRNARAQ
  SRKQRQLKADAKKAIGRLQLRTLKQGDKEIGPDGDSCAVCIELYKPNDLVRILTCNHIFH
  KTCVDPWLLEHRTCPMCKCDILKALGIEVDVEDGSVSLQVPVSNEISNSASSHEEDNRSE
  TASSGYASVQGTDEPPLEEHVQSTNESLQLVNHEANSVAVDVIPHVDNPTFEEDETPNQE
  TAVREIKS
• Function: E3 ubiquitin-protein ligase that catalyzes 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains formation. Functions as an inhibitor of cytokine gene transcription. Inhibits IL2 and IL4 transcription, thereby playing an important role in the induction of the anergic phenotype, a long-term stable state of T-lymphocyte unresponsiveness to antigenic stimulation associated with the blockade of interleukin production. Ubiquitinates ARPC5 with 'Lys-48' linkages and COR1A with 'Lys-63' linkages leading to their degradation, down-regulation of these cytosleletal components results in impaired lamellipodium formation and reduced accumulation of F-actin at the immunological synapse. Functions in the patterning of the dorsal ectoderm; sensitizes ectoderm to respond to neural-inducing signals.
• Reactome Pathway:
  Ovarian tumor domain proteases (R-HSA-5689896)
  Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[2]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[1]
Hypospadias	DIS48CCP	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[5]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[6]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[16]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase RNF128 (RNF128).	[20]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of E3 ubiquitin-protein ligase RNF128 (RNF128).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of E3 ubiquitin-protein ligase RNF128 (RNF128).	[19]

References

• [1] Isoforms of RNF128 Regulate the Stability of Mutant P53 in Barrett's Esophageal Cells.Gastroenterology. 2020 Feb;158(3):583-597.e1. doi: 10.1053/j.gastro.2019.10.040. Epub 2019 Nov 9.
• [2] RNF128 Promotes Invasion and Metastasis Via the EGFR/MAPK/MMP-2 Pathway in Esophageal Squamous Cell Carcinoma.Cancers (Basel). 2019 Jun 18;11(6):840. doi: 10.3390/cancers11060840.
• [3] Genome-wide association analyses identify variants in developmental genes associated with hypospadias.Nat Genet. 2014 Sep;46(9):957-63. doi: 10.1038/ng.3063. Epub 2014 Aug 10.
• [4] Downregulation of RNF128 activates Wnt/-catenin signaling to induce cellular EMT and stemness via CD44 and CTTN ubiquitination in melanoma.J Hematol Oncol. 2019 Mar 4;12(1):21. doi: 10.1186/s13045-019-0711-z.
• [5] Dysregulation of anergy-related factors involved in regulatory T cells defects in Systemic Lupus Erythematosus patients: Rapamycin and Vitamin D efficacy in restoring regulatory T cells.Int J Rheum Dis. 2016 Dec;19(12):1294-1303. doi: 10.1111/1756-185X.12509. Epub 2014 Oct 28.
• [6] Upregulation of GRAIL is associated with remission of ulcerative colitis.Am J Physiol Gastrointest Liver Physiol. 2008 Jul;295(1):G163-G169. doi: 10.1152/ajpgi.90242.2008. Epub 2008 May 8.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [17] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.